Imine enolates, chiral

When either or both of the reaction components has a chiral substituent, the reaction can be enantioselective (only one of the four diastereomers formed predominantly), and this has been accomplished a number of times. Enantioselective addition has also been achieved by the use of a chiral catalyst and by using optically active enamines instead of enolates. Chiral imines have also been used. ... 

Since then, efficient catalytic asymmetric methods have been developed for the addition of silyl enol ethers or silyl ketene acetals to imines with chiral metal catalysts [29-34], Recently, direct catalytic asymmetric Mannich reactions which do not require preformation of enolate equivalents have appeared. 

Aza-enolates derived from imines were introduced in chapter 10. It is easy to see that imines from chiral amines might well be used to make aza-enolates that would react asymmetrically with electrophiles. Among the most famous examples are the hydrazones SAMP and RAMP derived by Enders from proline.3 The starting material derived from natural (S )-(-)-proline 17 is called SAMP 18 and the one derived from unnatural (R)-(+)-proline is RAMP. The reactions of the two are identical except that they lead to products of opposite chirality. 

Quinazolinone annelation of the 0-protected chiral pyrolidinone 74 (derived from L-aspartic acid) forms pyrrolo[2,l-fc]quinazohn-9(lH)-one 75 subsequent desilylation affords (S)-(-)-vasicinone 10, which is identical with the natural /-product (Scheme 16) [212,213]. Asymmetric oxidation of de-oxyvasicinone 11 (via the imine enolate) with either (R)- or (S)-Davis ox-aziridine reagent (lO-camphorsulfonyloxaziridine) [214,215] provides a convenient route to both enantiomers, thus confirming the recently revised stereochemistry of natural vasicinone (Scheme 16) [212,213]. Recently another approaches to optically active pyrrolo[2,l-fo]quinazolinones 10 have been reported by Kamal et al. (lipase-catalyzed resolution) [56], and Argade et aL (asymmetric synthesis from (S)-acetoxysuccinic anhydride) [216]. One-pot synthesis of 11, and related alkaloids has been also developed by utilizing microwave irradiation by Liu et al. [217]. Biogenetically patterned short-step synthesis of pyrroloquinazolinone alkaloids is well established by On-aka [218], and for many other synthesis, see the references cited in these papers. 

An alternative approach is to have the chiral auxiliary on the enolate. Sweeney has reported the addition of bromoacyl sultam 102 to phosphonyl imines 103, which afforded the cis- or trans-aziridines with high levels of diastereoselectivity depending on the imine substituent (Scheme 1.30) [55]. 

Darzens reactions between the chiral imine 52 and a-halo enolates 53 for the preparation of nonracemic aziridine-2-carboxylic esters 54 (Scheme 3.17) were studied by Fujisawa and co-workers [61], It is interesting to note that the lithium enolate afforded (2K,3S)-aziridirie (2i ,3S)-54 as the sole product, whereas the zinc enolate give rise to the isomer (2S,3i )-54. The a-halogen did not seem to affect the stereoselectivity. 

An interesting example from carbohydrate chemistry is the boron trifluoride-diethyl ether complex catalyzed nucleophilic addition of silyl enol ethers to chiral imines (from n-glyceralde-hyde or D-serinal)22. This reaction yields unsaturated y-butyrolactones with predominantly the D-arabino configuration (and almost complete Cram-type erythro selectivity). 

A proline derived chiral nickel complex 1 may be used instead of oe,/J-unsaturated esters of lactones modified with a chiral alcohol as the Michael acceptor. The a,(9-unsaturated acid moiety in 1 reacts with various enolates to afford complexes 2 with diastereomcric ratios of 85 15 to 95 5. Hydrolysis of the imine moiety yields the optically active /(-substituted r-alanines. A typical example is shown296. 

The asymmetric synthesis of 2,3-diamino acids can be accomplished by the addition of chiral enolates to prochiral imines. For example, reaction of morpholine-2-one 103, derived from (S)-phenylglycinol, with N-benzyl ben-zaldimine in the presence of pyridine and para-toluenesulfonic acid at high... 

Scheme 17 Asymmetric synthesis of 2,3-diaminoacids by the addition of a chiral imi-noester enolate to achiral imines...

Scheme 27 Addition of nitronates, enolates and silyl ketene acetals to chiral a-amino imines and iminium ions...

Ojima, 1., Habus, 1., Zhao, M. (1991) Efficient and Practical Asymmetric Synthesis ofthe Taxol C-13 Side Chain, N-Benzoyl-(2R,3S)-3-phenylisoserine, and its Analogues via Chiral 3-Hydroxy-4-aryl-b-lactams Through Chiral Ester Enolate-Imine Cyclocondensation. Journal of Organic Chemistry, 56, 1681-1683. 

Hagiwara et al.107 reported the chiral Pd(II) complex-catalyzed asymmetric addition of enol silyl ethers to imines, based on the belief that Pd(II) enolate was involved in the reaction. They found that with compound 171a as the catalyst, very low enantioselectivity was obtained in the asymmetric reactions between silyl enol ether and imine compounds (Scheme 3-58). However, in the... 

A stochiometric approach was applied by Van Koten and co-workers [29], who used chiral carbosilane dendrimers as soluble supports in the in situ ester enolate-imine condensation in the synthesis of /Mactams (e.g. 19, Scheme 20). The formation of the /Mactam products proceeded with high trans selectivity, and with the same level of stereoinduction as was earlier established in reactions without the dendritic supports, (i.e. the use of the enantiopure dendritic support did not affect the enantioselectivity of the C-C bond formation). After the reaction, the dendrimer species could be separated from the product by precipitation or GPC techniques and reused again. 

TiCl, on the silyl ketene acetal however, other data suggest that metal enolates may not be involved (73b). In subsequent studies, this reaction has been extended to chiral imines (81,82). 

Potassium enolates derived from the chiral Schiff bases obtained by reaction of racemic a-amino esters with 2-hydroxypinan-3-one undergo diastereoselective protonation, as evidenced by release of optically active a-amino esters on subsequent cleavage of the imine (Scheme 5). ... 

Enantiomerically pure trans-2-phenylcyclohexanol, first used by Whitesell as a chiral auxiliary has become a popular reagent in a number of asymmetric transformations. Some recent applications include asymmetric azo-ene reactions, [4 + 2]-cycloaddition reactions, ketene-olefin [2 + 2]-reactions, enolate-imine cyclocondensations, Pauson-Khand reactions," palladium annulations and Reformatsky reactions. Despite its potential, use of this chiral auxiliary on a preparative scale is currently limited by its prohibitive cost. 

Oxidation of chiral sulfonimines (R"S02N=CHAr)and chiral sulfamyl-imines (R RNS02N=CHAr)affords optically active 2-sulfonyloxaziridines and 2-sulfamyloxaziridines, respectively. These chiral, oxidizing reagents have been used in the asymmetric oxidation of sulfides to sulfoxides (15-68% ee), 11-13 selenides to selenoxides (8-9% ee] enolates to a-hydroxycarbonyl compounds (8-37% ee) and in the asymmetric epoxidation of alkenes (15-40% ee)... 

Further process optimization by Thiruvengadam and co-workers (Thimvengadam et al., 1999), led to a novel, stereoselective, scalable two-step process devoid of chromatography for chiral 2-azetidinone construction (Scheme 13.4). As above, the titanium-enolate of chiral oxazolidinone 11a was preformed, but now when reacted with well behaved imines of type 16, affords the unexpected anti-addition product. This surprising result was further supported by careful comparison to minor antiproducts obtained in the earlier aldol-addition methodology and determination that the major product was indeed 17a (undesired RSR series). Adjustment of the oxazolidinone absolute stereochemistry to the fortuitously less expensive 2S-series afforded the desired diastereo-mer 17b in 95% de and in 50-70% yield. Recrystallization improved the stereochemical purity to >99% de. 

The chiral enolate-imine addition methodology was examined in detail (Thiruvengadam et al., 1999). Enolate formation proceeds to completion within an hour at temperatures from — 30 to 0°C with either 1 equiv. TiCl4 or TiClaO-iPr (preformed or prepared in the presence of substrate by addition of TiCl4 and followed by a third of an equivalent Ti(0-iPr)4 and two equivalents of a tertiary amine base). Unlike the aldol process with the same titanium enolate, the nature of the tertiary amine base had no effect on the diaster-eoselectivity. The diastereoselectivity is maximized by careful control of the internal temperature to below — 20°C during the imine addition (2 equiv.) as well as during the acetic acid quench. The purity of the crude 2-amino carboxamide derivatives (17a or... 

In the course of examining the CAI effect of conformational restriction of the C3-side-chain, intermediate 24 was prepared. Shankar and co-workers (Shankar et al., 1996) demonstrated that 10, a key intermediate in the research synthesis could be accessed by Wacker oxidation of olefin 24 (Scheme 13.7). Additionally, an alternative chiral variant of the well-precedented addition of zinc enolates to imines was demonstrated. Treatment of the bromoacetate 25, derived from 8-phenylmenthol with zinc and sonication followed by imine addition afforded 26 in 55% yield with greater than 99% de. Ethyl magnesium promoted ring-closure followed by C3 alkylation with 28, intercepts the previously demonstrated route through formation of olefin 24 (Shankar et al., 1996). 

Wu and co-workers (Wu et al., 1999) have demonstrated a novel chiral lactone enolate-imine process to access 2-azetidinone diols such as 35 (Scheme 13.10). Treatment of 34 with LDA at — 25°C in THF followed by addition of imine 3, afforded only trace product. Addition of HMPA or the less toxic DMPU during the lithium enolate formation step improved the yield and the trans cis diastereoselectivity ( 90 10). Recrystallization improved the purity to >95 5 trans cis 2-azetidinone. Addition of an equivalent of lithium bromide accelerates the rate of ring closure, presumably by destabilizing the intermediate lithium aggregates. Side-chain manipulation of 35 was accomplished by sodium... 

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